A Drug Interaction Study to Assess the Effect of LY317615 on the Metabolic Pathway of Warfarin

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The purpose of this study is to assess the effect of enzastaurin (LY317615), on a protein (enzyme CYP2C9) which is involved in the metabolic pathway of warfarin in patients with solid tumors or lymphomas. Information about any side effects that may occur will also be collected. This is a drug interaction study so the treatment of the disease will not be the main purpose of the study.

This is a Phase 1, open label, fixed sequence, 2 period study conducted in patients with solid tumors or lymphomas. The duration of participation in this study will be up to approximately 38 days not including screening, after which patients will be allowed to continue receiving enzastaurin. There is no planned duration for the extension phase of this study; patients will be allowed to continue to receive enzastaurin until fulfilling one of the criteria for discontinuation, such as unacceptable toxicity or disease progression.

Pharmacokinetics: time of maximal plasma concentration (tmax) of S-warfarin and R-warfarin [ Time Frame: Period 1 and 2: Predose, up to 96 hours post dose ]

Pharmacokinetics: area under the plasma concentration-time curve from time zero to infinity [AUC(0-∞)] of S-warfarin and R-warfarin [ Time Frame: Period 1 and 2: Predose, up to 96 hours post dose ]

Secondary Outcome Measures :

Pharmacokinetics: maximum observed drug concentration (Cmax) at steady state of enzastaurin, its principle metabolites and total analyte [ Time Frame: Period 2: Predose, up to 24 hours post dose on Days 14 and 15 ]

Pharmacokinetics: time of maximal plasma concentration (tmax) of enzastaurin, its principle metabolites and total analyte [ Time Frame: Period 2: Predose, up to 24 hours post dose on Days 14 and 15 ]

Pharmacokinetics: area under concentration-time curve over a dosing interval at steady state (AUCt,ss) of enzastaurin, its principle metabolites and total analyte [ Time Frame: Period 2: Predose, up to 24 hours post dose on Days 14 and 15 ]

Pharmacokinetics: average concentration during a dosing interval steady state (Cav,ss) of enzastaurin, its principle metabolites and total analyte [ Time Frame: Period 2: Predose, up to 24 hours post dose on Days 14 and 15 ]

Pharmacodynamics: Maximum International normalised ratio (INRmax) following warfarin alone [ Time Frame: Period 1: Baseline, predose on day 1, up to 96hours post dose ]

Pharmacodynamics: area under International normalised ratio-time curve AUC(INR) following warfarin alone [ Time Frame: Period 1: baseline, predose on Day 1, up to 96 hours post dose ]

Pharmacodynamics: Maximum International normalised ratio (INRmax) following concomitant administration of warfarin and enzastaurin [ Time Frame: Period 2: predose on Day 15, up to 96 hours post warfarin dose ]

Pharmacodynamics: area under International normalised ratio-time curve AUC(INR) following concomitant administration of warfarin and enzastaurin [ Time Frame: Period 2: predose on Day 15, up to 96 hours post warfarin dose ]

Pharmacodynamics: International normalised ratio (INR) following enzastaurin alone [ Time Frame: Period 2: Day 14 predose and up to 4 hours post dose ]

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Ages Eligible for Study:

18 Years to 60 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Have given written informed consent approved by Eli Lilly and Company (Lilly) and the ethical review board (ERB) governing the site

Have a histologic or cytologic diagnosis of cancer (lymphoma or solid tumor), with clinical or radiologic evidence of locally advanced and/or metastatic disease for which no life-prolonging therapy exists (Note: patients with glioblastoma, known central nervous system (CNS) metastases and other hematologic malignancies [except lymphoma] are excluded from this study)

Men or women with reproductive potential must use an approved contraceptive method, if appropriate, during and for 3 months after discontinuation of study treatment. All methods of contraception should meet the criteria of highly effective contraceptives(failure rate of <1% per year) such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence, or vasectomized partner. Women with childbearing potential must have a negative serum pregnancy test ≤3 days prior to the first dosing day in the study (Period 1, Day 1).

Have a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale and, in the investigator's opinion, are suitable for participation in the study

Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, anticancer hormone therapy, or other investigational therapy for at least 30 days prior to study entry (6 weeks for mitomycin-C or nitrosoureas), and have recovered from the acute effects of therapy

For patients with hormone refractory prostate cancer, the following exception is permitted:

Patients receiving luteinizing hormone-releasing hormone (LHRH) analogue therapy (leuprolide, goserelin, or triptorelin) prior to starting this study should have that therapy continued while on this study.

In addition, patients who have received nonsteroidal antiandrogen therapy in the form of bicalutamide should have discontinued therapy at least 6 weeks prior to study entry (4 weeks if on flutamide or nilutamide).

Have adequate organ function including:

Bone Marrow Reserve: absolute neutrophil count (ANC) ≥1.5 x 109/L prior to treatment, platelets ≥100 x 109/L, and hemoglobin ≥10 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Patients may be allowed erythropoietin of choice as per standard of care.

Hepatic: bilirubin within 1.5 times the upper limit of normal (ULN), and transaminases ≤2.5 times ULN or ≤5 times ULN when liver metastases are known.

Renal: serum creatinine ≤1.5 mg/dL.

Electrolytes: Patients may be entered into the study, if the investigator's opinion is that any electrolyte disorders, including potassium <3.4 mEq/L, calcium <8.4 mg/dL, or magnesium <1.2 mEq/L, may be appropriately managed and stabilized by the time of the laboratory evaluation on the baseline day in Period 1. If electrolytes have not been stabilized during this time, the patient will be discontinued from the study.

Coagulation: normal PT/INR and aPTT

Have an estimated life expectancy, in the judgment of the investigator, which will permit the patient to complete the drug interaction phase and at least 1 cycle of the safety extension phase (if the patient were to participate in the safety extension)

Exclusion Criteria:

Have received treatment within 28 days of the initial dose of study drug with an experimental agent for non-cancer indications that has not received regulatory approval for any indication

Patients with glioblastoma, Central Nervous System (CNS) metastases, or hematologic malignancies other than lymphoma are excluded from this study.

Serious concomitant systemic disorder, including active infection, incompatible with the study (at the discretion of the investigator)

Cardiac: Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV. Patients with a QTcB prolongation >450/470 msec (males/females) and patients who have a congenital long-QT-syndrome in their own or family medical history should be excluded at the investigator's discretion. Patients with intraventricular conduction delays (for instance, right or left bundle branch blocks) should also be excluded.

It is recommended that patients with baseline arrhythmias (persistent or paroxysmal ventricular or supraventricular arrhythmias, including atrial fibrillation [occasional premature atrial contractions [APCs] or premature ventricular contractions [PVCs] are acceptable] or bradycardia (heart rate <50) be excluded, at the investigator's discretion.

Known family history of unexplained sudden death

Personal history of unexplained syncope within the last year

The use of concomitant medications that prolong the QT/QTc interval

Patients with complete gastrectomy or other significant GI diseases that, in the investigator's opinion, may significantly impact drug absorption

Patients on total parenteral nutrition (TPN)

Inability to swallow tablets

Women who are lactating

Patients with known allergies to enzastaurin or warfarin

Patients with warfarin-related skin necrosis

Patients who are known CYP2C9 poor or intermediate metabolizers

Drugs that are known inhibitors or inducers of CYP3A are specifically excluded. Foods that are known inhibitors of CYP3A (for example, grapefruit or grapefruit juice or Seville oranges or Seville orange juice) are also specifically excluded during Period 1 and Period 2 of the study.

Drugs with narrow therapeutic windows and that are also known substrates of CYP2C9, CYP2C8, CYP2C19, and CYP3A are excluded.

Use of any known inducers or inhibitors of CYP2C9 within 30 days (or at least 5 half-lives, whichever is shorter) prior to enrollment. Drugs that are inhibitors or inducers of CYP2C9 are also excluded throughout Periods 1 and 2. Drugs that are known to increase the hypoprothrombinemic effect of warfarin are excluded prior to enrollment and throughout Periods 1 and 2.

Use of other anticoagulants or antithrombolytics within 14 days prior to screening or during Periods 1 and 2

Use of low-dose aspirin (or higher doses) within 14 days prior to screening and during Period 1 and 2 of the study (allowed during continued safety extension phase)

Use of high-dose acetaminophen (paracetamol) within 14 days of Period 1 and during Period 1 and 2 of the study

Patients who have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females) or patients unwilling to stop alcohol consumption for the duration of the drug interaction phase (Periods 1 and 2) of the study (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).

Use of drugs of abuse, as evidenced by history, and/or positive findings on urinary drug screening, unless prescribed by a physician (for example, narcotic pain medication)

Failure for any reason to satisfy the investigator for adequate fitness to participate in the study